title: Sp-2-propylthio-ATP-α-B and Sp-2-propylthio-ATP-α-B,β-γ-dichloromethylene are novel potent and specific agonists of the human P2Y₁₁ receptor.
abstract: The human P2Y₁₁ nucleotide receptor mRNA was found in virtually all human tissues, and the receptor serves many physiological roles, such as immune response regulation. The Ala-87-Thr-P2Y₁₁ receptor single nucleotide polymorphism was linked to increased risk for acute myocardial infarction. To facilitate the development of new therapeutic applications involving cells expressing several P2 receptor subtypes, the availability of specific and potent agonists is mandatory. Here, we synthesized a series of novel adenine nucleotide derivatives, based upon the potent P2Y₁₁ receptor agonists AR-C67085. Features of the novel nucleotide derivatives are a propylthio substitution at C2-adenine and a Pα-borano or Pα-thio substitution of non-bridging oxygen atom. The latter substitutions introduce a chiral center at the α-phosphate. Sp-isomers of Pα-borano- and Rp-isomers of Pα-thio-substituted nucleotides are preferred by the P2Y₁₁ receptor. As recently reported by us, diastereoselectivity of the P2Y₁₁ receptor is opposite to that of the P2Y₁ receptor. Therefore, we exploit this characteristic to increase nucleotide selectivity. At the P2Y₁₁ receptor, the Sp-isomers of 2-propylthio-ATP-α-B (2B) and 2-propylthio-ATP-α-B,β-γ-dichloromethylene (4B) were the most potent of the novel nucleotide series, with EC₅₀ values of 0.03 μM for both, being ca. 80-fold more potent than 2-propylthio-ATP and ATP (EC₅₀ = 2.6 μM). We conclude that the borano-substitution at the α-phosphate of 2-propylthio-ATP enhances nucleotide potency at the P2Y₁₁ receptor. The combination with a Pβ-Pγ-dichloromethylene group in 4B results in a nucleotide, which shows higher selectivity for the P2Y₁₁ receptor over the P2Y₁₁ receptor than 2B making it the most promising of the novel P2Y₁₁ receptor agonists.
authors.affiliation: Institute for Neurobiochemistry, Faculty of Medicine, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haas
authors.forename: Idan
authors.initials: I
authors.lastname: Ben-Moshe
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D058910:Purinergic P2 Receptor Agonists / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000187:drug effects* / Q000235:genetics
chemical_list: C109734:P2RY11 protein, human; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate
keywords: 2-MeS-ATP; 2-methylthio-adenosine-5′-triphosphate; 2-propylthio-ATP-β-γ-dichloromethylene; 3′-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate; ADP; ADPβS; AR-C67085; ATP; ATPγS; BzATP; IBMX; IP(3); Nucleotide receptor; P2Y receptor; Purinergic agonist; UTP; UTR; adenosine-5′(2-thio)diphosphate; adenosine-5′(3-thio)-triphosphate; adenosine-5′-diphosphate; adenosine-5′-triphosphate; dATP; desoxy-adenosine-5′-triphosphate; e-NTPDase; ecto-nucleoside-triphosphate-diphosphohydrolase; inositol-1,4,5-trisphosphate; isobutyl-methyl-xanthine; untranslated region; uridine-5′-triphosphate